Parkinson's disease is caused by a disturbed dopaminergic neurotransmission in the basal ganglia, generally as a result of increasing destruction of dopaminergic neurons, occurring first in the substantia nigra, and subsequently over the course of the disease in other areas as well. In advanced cases, an increasing lack of noradrenaline (e.g., in the locus caeruleus) has been shown. Even in the early stages of the disease, a very clear decrease in tyrosine hydroxylase activity is also seen; it is interesting that this enzyme activity is also greatly reduced in other systems and organs (e.g., in the adrenal medulla) (see table 3 of Birkmayer and Riederer, Parkinson's Disease, second edition, page 34, Springer Verlag Vienna 1985, reproduced below as Table 1).
TABLE 1 ______________________________________ Tyrosine Hydroxylase in Various Brain Areas in Parkinson's Disease Brain Areas Control Parkinsonian ______________________________________ N. caudatus (15) 27.8 .+-. 2.3 3.5 .+-. 1.0 (6)* Puramen (5) 16.2 .+-. 5.9 1.2 .+-. 0.4 (6)* S. nigra (4) 19.4 .+-. 6.2 4.9 .+-. 1.8 (4)* L. caeruleus (4) 3.3 .+-. 0.1 2.0 .+-. 0.6 (2) N. ruber (5) 5.7 .+-. 1.9 2.1 .+-. 1.4 (3) Raphe + R.F. (4) 0.9 .+-. 0.6 1.5 .+-. 0.4 (5) Hypothalamus (5) 3.1 .+-. 1.0 1.5 .+-. 0.3 (3) C. mamillare (5) 0.6 .+-. 0.4 0.5 .+-. 0.9 (2) N. accumbens (5) 2.0 .+-. 0.7 2.7 .+-. 2.2 (3) Adrenal medulla (5) 186.2 .+-. 5.5 49.7 .+-. 12.4 (4) ______________________________________ Number of patients in parentheses. Mean value .+-. sem (nmole) Dopa/g-tissue hour) *p&lt;0.01.
In conventional therapy, the missing or reduced dopaminergic activity is replaced by the dopamine precursor L-DOPA; when this effect decreases, the L-DOPA effect can be increased further by specific suppression of the enzyme monoamine oxidase (MAO-8), which breaks down the dopamine.
But after years of use these treatment strategies-although the life expectancy of the patients was improved--often led to severe and unpredictable fluctuations in mobility (fluctuations, on-off phenomena), which appreciably impair the patients' quality of life. These fluctuations can be prevented or at least reduced partially by timely use of post-synaptic agonists such as lisuride.
It has been suggested that the sudden reduction in mobility is related to a temporary depletion of tyrosine hydrolylase (Birkmayer and Riederer, Parkinson's Disease, second edition, page 81, Springer Verlag, Vienna, 1985). However, an increased load of tyrosine hydroxylase can also be postulated, based on the biochemistry of some of the standard therapies.